Etiological Factors in ADHD


At the present time it must be acknowledged that we do not know the specific
cause(s) of the...
•   Twin studies have suggested that concordance rates for monozygotic
       (identical) twins is around 80% while concor...
It has been suggested that probably no more than 4% of the variance in the
expression of ADHD symptoms can be accounted fo...
This does not mean, however, that neurological facrors are not involved.

NEUROPSYCHOLOGICAL TEST FINDINGS

As noted earli...
While results have varied somewhat, the most consistent pattern has been lower
amplitude responses in certain portions of ...
anterior right frontal regions, a smaller caudate nucleus, and smaller
       golbus pallidus regions that normal controls...
Here he suggests:

It should be evident from the research…that neurological and
genetic factors make a substantial contrib...
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ADHDEtiology.doc

  1. 1. Etiological Factors in ADHD At the present time it must be acknowledged that we do not know the specific cause(s) of the condition we now refer to as ADHD. Nevertheless, in recent years, we have accumulated a great deal of information regarding factors that seem to contribute to the development of this disorder. Research findings, however, are often inconsistent and don’t always fit neatly together. And, many of the studies in this area are correlational in nature, making it impossible to infer causality. Despite these limitations we have learned a great deal about potential contributors to the development of the disorder in recent years. Available findings seem to strongly implicate genetic and neurological factors. PREGNANCY AND BIRTH COMPLICATIONS As has been noted earlier, pregnancy and birth complications have been found in some, but not all studies, to bear a statistically significant relationship with ADHD. We have already touched on this is discussing risk factors. Here ADHD has been shown to be associated with: • Unusually long or short labor • Fetal distress (from a variety of factors) • Forceps delivery • Toxemia • Eclampsia • Low birthweight • Birth during the month of September. It is suggested that season of birth may serve to influence the timing of seasonally mediated viral infections to which mothers and fetuses may have been exposed and this may account for approximately 10% of the cases of ADHD. GENETIC FACTORS We have already discussed the considerable contribution of genetics to ADHD. • Between 10 and 35 per-cent of the immediate family members of children with ADHD also display this disorder. • Risk for siblings of children with disorder is approximately 32% • If a parent has ADHD the risk to offspring is on the order of 57%
  2. 2. • Twin studies have suggested that concordance rates for monozygotic (identical) twins is around 80% while concordance is approximately 30% for dizygotic (fraternal) twins. • Overall, twin studies suggest an average heritability of .80. • Studies resulting from the Human Genome Project have also identified specific genes that are thought to be related to this disorder. Included here is the “dopamine type 2 gene” which has been found to be related to ADHD as well as Tourette’s and alcoholism. More recently have been the isolation of a "dopamine transporter gene" and a “dopamine repeater gene”, both of which are related to a neurotransmitter that has been heavily implicated in ADHD. • The "dopamine repeater gene (which is characterized by multiple copies) is especially of interest in that it has previously also been associated with the personality trait of novelty-seeking and has been found to be related to post-synaptic sensitivity in the frontal and prefrontal cortical regions and to be associated with executive functions. This gene has been found to be associated with ADHD in multiple studies with children, adolescents, and adults. With developments in molecular genetics occurring at an increasingly rapid rate, it is conceivable that, in the fairly near future, we may have genetic tests that can provide early screening for ADHD and possibly associated comorbidities. Genetic factors are clearly strongly implicated in the development of this disorder. Indeed, hereditary is one of the most well supported etiological factors in the development of ADHD. ENVIRONMENTAL TOXINS One such environmental factor which may be neurologically compromising is environmental lead. In animal studies with rats it has been found that increased lead burdens are associated with increased hyperactive behavior. While the relationship between lead burden and ADHD in children is not necessarily a strong one, there is some evidence that it may be a contributing factor in the development of hyperactive behavior and other symptoms of ADHD. As Barkley has noted, studies have typically found "small and consistent relationships" between lead levels and ADHD. It must be noted, however, that even with relatively high lead burdens, less than 38% of children are rated as hyperactive by teachers. Most lead poisoned children do not develop ADHD. And, most ADHD children do not have significantly elevated lead burdens - although at least one study has found them to have higher lead burdens than normals.
  3. 3. It has been suggested that probably no more than 4% of the variance in the expression of ADHD symptoms can be accounted for by lead levels. Lead levels may simply be one of a number of factors that can contribute to hyperactivity under some circumstances. Other types of toxins that have been found to be associated with ADHD are prenatal exposure to alcohol and cigarette smoke. Parents of children with ADHD do consume more alcohol and smoke more tobacco that those in control groups, even when not pregnant. Most studies have not studied children actually diagnosed as ADHD and most have not considered the presence of ADHD in parents. There is at least one study which suggests that the relationship between smoking during pregnancy and ADHD holds even after controlling for symptoms of ADHD in the parent. A major problem with lead, alcohol and smoking studies is the failure of studies to use standard diagnostic criteria and to control for parental ADHD. THE ROLE OF NEUROLOGICAL IMPAIRMENT Brain damage of some sort has long been thought to be a contributor to ADHD. And, there is evidence that factors that can result in brain damage are associated with ADHD. • For example, anoxia, is associated with increased frequencies of hyperactivity and attentional problems. • ADHD also occurs more often in children with seizure disorders, who can be presumed to have neurological involvement. • As was noted earlier, diseases such as encephalitis can also result in symptoms of ADHD as can various types of infections. • And, it is also clear that ADHD can result from significant head injury. Such findings suggest that neurological insult can result in an increased probability of developing ADHD. However, most children with ADHD do not have a significant history of brain injury. Indeed, such injuries are unlikely to account for the development of ADHD in most children. In an early review of this literature by Dubey (1979) it was suggested that probably 95% of hyperactive children show no evidence of documentable brain damage. While children with ADHD often show many “soft neurological signs” they typically do not show evidence of frank brain damage.
  4. 4. This does not mean, however, that neurological facrors are not involved. NEUROPSYCHOLOGICAL TEST FINDINGS As noted earlier, investigators have, for many years, noted the similarities between symptoms of ADHD and characteristics of individuals with lesions or injuries to the frontal lobes and to the prefrontal context specifically. Both children and adults suffering injuries to the prefrontal regions demonstrate deficits in sustained attention, inhibition, regulation of emotion and motivation, and the capacity to organize behavior across time. Given the similarity between symptoms of frontal lobe lesions and symptoms of ADHD, it is not surprising that a large number of studies have used neuropsychological tests thought to be sensitive to frontal lobe functions. These studies have often found significant degrees of impairment on these tests. Results often seem to suggests disinhibition of behavioral responses and problems in working memory, planning, verbal fluency, perserveration, motor sequencing, and other frontal lobe functions. These are characteristics often categorized under the heading of executive functions. Adults with ADHD have also been found to show similar types of deficits. Not only do siblings of children with ADHD, who have ADHD themselves, show similar executive functioning deficits but even those siblings of ADHD children who do not have ADHD, appear to have milder yet significant impairments in these same executive functions. These findings suggest a possible genetic risk for executive function deficits in families that have ADHD children , even if symptoms of ADHD are not fully manifest in family members. Barkley suggests that, taken together, findings in this area are impressive in suggesting that dysfunction of the prefrontal lobes (inhibition and executive functions) is a likely basis for explaining ADHD. PSYCHOPHYSIOLOGICAL STUDIES As we have previously noted, studies using psychophysiological measures of nervous system electrical activity measured in different ways (EEG, GSR, Heart rate deceleration, etc.) have been somewhat inconsistent in findings group differences between ADHD and normal control children. But, when differences from normals are found, they are consistently in the direction of diminished arousal or arousability in children with ADHD. There have been a number of studies of Evoked Potentials with ADHD children where EP's have been obtained while children were performing vigilance tasks.
  5. 5. While results have varied somewhat, the most consistent pattern has been lower amplitude responses in certain portions of their ERP's which are thought to be related to functioning of the prefrontal areas. These types of responses are said to suggest an underresponsiveness of ADHD children to stimulation. Similar findings have been obtained using other psychophysiological indices of responsivity. It is interesting to note that this underresponsiveness has been shown to be attenuated with stimulant medication. STUDIES OF CEREBRAL BLOOD FLOW Studies of cerebral blood flow in ADHD and normal children have consistently shown decreased blood flow to the prefrontal regions and pathways connecting these regions to the limbic system via the striatum and specifically its anterior region (the Caudate Nucleus). Most recently studies using PET scan technology to assess cerebral glucose metabolism in the frontal regions have found diminished metabolism in, at least adults and adolescent females with ADHD. Significant correlation's between diminished metabolic activity in the left anterior frontal region and severity of symptoms in adolescents with ADHD have also been demonstrated. It can be noted that this demonstration of a relationship between decreased metabolic activity of certain brain regions and severity of ADHD symptoms is crucial to documenting the relevance of brain activation and behaviors associated with ADHD. CT SCANS The gross structure of the brain has not been shown to be significantly different for children with ADHD and normal children. MRI STUDIES More fine grained analyses using higher resolution MRI's have suggested differences, however. • Early studies found differences in the Corpus Callosum, with this structure being smaller in children with ADHD. However, this has not always been replicated in more recent investigations. • Other MRI studies have found children with ADHD to have a smaller left caudate nucleus than did normal children. These findings are consistent with the results of earlier blood flow studies suggesting lower levels of activation in this specific area in children with ADHD. • Several more recent MRI studies, with larger samples, have replicated these early results by finding that ADHD children had significantly smaller
  6. 6. anterior right frontal regions, a smaller caudate nucleus, and smaller golbus pallidus regions that normal controls. • Research has also found decreased cerebellar volume in children with ADHD. Despite limitations inherent in much of the work in this area it is suggested that the literature, taken together, suggests that abnormalities in the development of the frontal-striatal regions probably underlie the development of ADHD. It is noteworthy that no neuroimaging studies have found evidence of "brain damage" in any of the structures identified as differentiating between ADHD children and normals. The regions identified as being related to ADHD have typically been found to just be smaller. Barkley suggests that when differences in brain structures are found, they are likely to result in abnormalities in brain development within particular regions, that the causes of this are unknown, but they are probably under genetic control. NEUROTRANSMITTER DEFICIENCIES The possibility of a neurotransmitter dysfunction in children with ADHD has been suggested for many years. This notion seemed to originate from observations of the response of children with ADHD to different type of stimulant drugs. The fact that stimulant drugs increase dopamine has contributed to the neurotransmitter dysfunction hypothesis. The fact that normals respond to stimulants in a manner similar to ADHD children (although to a lesser degree), however, argues against using drug response to argue for a neurotransmitter abnormality. There is, however, direct evidence from studies of cerebral spinal fluid in ADHD and normal children which suggests decreased dopamine levels in ADHD children. There is also some evidence of a deficiency in the availability of norepinephrine in children with ADHD. PSYCHOSOCIAL FACTORS IN THE ETIOLOGY OF ADHD Little evidence for the role of psychosocial factors in the development of ADHD although factors such as parent child conflict may exacerbate problems in a child with ADHD. OVERVIEW OF FINDINGS REGARDING ETIOLOGY In reviewing the literature on the etiology of ADHD, Barkley highlights the role of biology in the development of ADHD.
  7. 7. Here he suggests: It should be evident from the research…that neurological and genetic factors make a substantial contribution to symptoms of ADHD and the occurrence of this disorder. A variety of genetic and neurological etiologies (e.g., pregnancy and birth complications, acquired brain damage, toxins, infections, and genetic effects) can give rise to the disorder through some disturbance in a final common pathway in the nervous system. That final common pathway appears to be the integrity of the prefrontal cortical-striatal network. It now appears that hereditary factors play the largest role in the occurrence of ADHD symptoms in children. It may be that what is transmitted genetically is a tendency toward a smaller and less active prefrontal-striatal network. The conditions can also be caused or exacerbated by pregnancy complications, exposure to toxins, or neurological disease. Social factors alone cannot be supported as causal in this disorder, but such factors may exacerbate the condition, contribute to its persistence, and more likely, contribute to the forms of comorbid disorders associated with ADHD. Cases of ADHD can also arise without genetic predisposition to the disorder provided the child is exposed to a significant disruption or neurological injury to this final common neurological pathway, but this would seem to account for only a small minority of ADHD children.

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